MODELING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY USING PRIMARY AND PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELLS
type: CreativeWork
description: Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant degenerative muscle disease with no cure or treatment. The genetic cause of FSHD is the reduction of the copy number of subtelomeric D4Z4 repeats at 4q35 encoding Double Homeobox 4 (DUX4) protein, which is a potent transcription factor that is toxic to the cell. Contractions lead to loss of repeat-induced silencing, allowing for transcription of DUX4. A common diagnostic method for FSHD shows demethylation of D4Z4 using gDNA of blood cells, and Kyba lab has shown that D4Z4 is demethylated in FSHD iPS cells, meaning that any cell type in an FSHD patient could be subject to deregulation by DUX4. DUX4 recruits p300 to induce global changes in histone acetylation, massively disrupting gene expression, thus pathology is not obviously exclusive to myogenic cells. Why the disease is muscle-specific and which cells in muscle may be deregulated by DUX4 are unknowns. Here are examined non-myogenic, muscle-associated cells derived from primary and induced pluripotent stem cells (iPSC) sources for evidence of DUX4 and target gene activation. To better visualize DUX4 expressing cells in vitro and in situ, these studies outline a visualization tool which uses signal amplification combined with a newly developed commercial antibody in both mouse and human tissue. Using this method, DUX4 positive cells have been identified in the human biopsy for the first time, providing a critical and novel insight into the cell types involved in FSHD pathogenesis. In a further attempt to model rare, muscle-associated populations in vitro, a novel fibroadipogenic progenitor (FAP) cell isolation method was developed, which is then used to obtain FAPs from patient biopsies. Using this new isolation method, FAPs were isolated from FSHD patients, and analysis of this rare cell population revealed that FSHD FAPs did not express DUX4 and its target genes, and that patient FAPs remained functionally normal if derived from intact musc…
abstract: Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant degenerative muscle disease with no cure or treatment. The genetic cause of FSHD is the reduction of the copy number of subtelomeric D4Z4 repeats at 4q35 encoding Double Homeobox 4 (DUX4) protein, which is a potent transcription factor that is toxic to the cell. Contractions lead to loss of repeat-induced silencing, allowing for transcription of DUX4. A common diagnostic method for FSHD shows demethylation of D4Z4 using gDNA of blood cells, and Kyba lab has shown that D4Z4 is demethylated in FSHD iPS cells, meaning that any cell type in an FSHD patient could be subject to deregulation by DUX4. DUX4 recruits p300 to induce global changes in histone acetylation, massively disrupting gene expression, thus pathology is not obviously exclusive to myogenic cells. Why the disease is muscle-specific and which cells in muscle may be deregulated by DUX4 are unknowns. Here are examined non-myogenic, muscle-associated cells derived from primary and induced pluripotent stem cells (iPSC) sources for evidence of DUX4 and target gene activation. To better visualize DUX4 expressing cells in vitro and in situ, these studies outline a visualization tool which uses signal amplification combined with a newly developed commercial antibody in both mouse and human tissue. Using this method, DUX4 positive cells have been identified in the human biopsy for the first time, providing a critical and novel insight into the cell types involved in FSHD pathogenesis. In a further attempt to model rare, muscle-associated populations in vitro, a novel fibroadipogenic progenitor (FAP) cell isolation method was developed, which is then used to obtain FAPs from patient biopsies. Using this new isolation method, FAPs were isolated from FSHD patients, and analysis of this rare cell population revealed that FSHD FAPs did not express DUX4 and its target genes, and that patient FAPs remained functionally normal if derived from intact musc…
author: Goloviznina, Natalya
language: en
keywords: Disease modeling, DUX4, FSHD, iPSC
date published: 2021-01
date modified: 2026-07-24T05:20:09Z
provider: University of Minnesota
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Minnesota

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property ID: Handle
value: https://hdl.handle.net/11299/253720